Is NPHP3 c.2475+3A>G pathogenic?

NPHP3 c.2475+3A>G is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-10). Very rare (popmax 0.00475%, nfe); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 c.2475+3A>G?

NPHP3 c.2475+3A>G is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 c.2475+3A>G in the general population?

NPHP3 c.2475+3A>G is very rare (popmax 0.00475%, nfe) (gnomAD).

NPHP3 c.2475+3A>G

rs201981598 · VCV1509799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.92 · evaluated, not missing
Pangolin	Δ0.47	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.5	GERP 1.6, phastCons 1
Non-coding constraint	Z 0.81	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	19.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00475% European (non-Finnish) · 56/1,179,266 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00366% 59/1,613,186 alleles · very rare exomes 59/1,460,924 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,058
Remaining individualsnot grpmax-eligible	0.0032%	31,231
African / African-American	0.00133%	75,022

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPHP3
Coding: c.2475+3A>G
MANE Select: NM_153240
dbSNP: rs201981598
Type: single nucleotide variant
Location: chr3:132692651 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

renal-hepatic-pancreatic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nphp3-c-2475-plus-3a-g (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown